Although the causes of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, and allergic diseases such as asthma and atopic dermatitis vary depending on their conditions, these diseases develop immunological disorders with symptoms in particular tissues or systemically caused by consequently aberrant immune responses. Conventionally, anti-inflammatory drugs such as steroid preparations and non-steroid anti-inflammatory drugs (NSAIDs) have been used to suppress the inflammatory responses resulting from over-responses of the immune system. However, these drugs are used only as symptomatic therapy, and their advantageous effects are limited and accompanied by no negligible adverse effects. Moreover, it has been known that disease-modifying anti-rheumatic drugs (DMARDs) that are commonly used as therapeutic agents for rheumatoid arthritis exert their effects by inhibiting differentiation/proliferation of lymphocytic cells that play a major role in immune responses. However, it is also known that serious adverse effects such as myelosuppression are induced because of their non-specific inhibition of various cell proliferations.
Recently, Fingolimod (or FTY-720), which was approved as a pharmaceutical agent for multiple sclerosis, is of particular interest as a pharmaceutical agent with a novel mechanism which regulates immunity without depletion of lymphocytic cells due to cell death and the like by controlling localization of lymphocytic cells. However, the use of Fingolimod has become controversial since serious adverse effects centered on the cardiovascular system such as bradycardia and cardiac arrhythmia have been observed (Non-Patent Document 1).
An S1P receptor is a G protein-coupled receptor that exists on cellular membranes, and five subtypes of the receptor (S1P1, S1P2, S1P3, S1P4, S1P5, AKA endothelial differentiation gene; EDG-1, EDG-5, EDG-3, EDG-6 and EDG-8) are identified. It is known that Fingolimod phosphorylated in vivo binds to S1P1, S1P3, S1P4, and S1P5 receptors, and acts as an agonist.
Phosphorylated Fingolimod sequestrates lymphocytic cells to secondary lymphoid tissues by inducing the accelerated cellular uptake mainly mediated by an S1P1 receptor, thus exerting potent immunosuppressive activity (Non-Patent Document 2). On the other hand, it has been shown that phosphorylated Fingolimod induces adverse effects such as bradycardia presumably mediated by an S1P3 receptor by animal experiments using an S1P1 receptor selective agonist, or by Patch clamp experiments using an S1P3 receptor selective antagonist, and moreover, by using an S1P3 receptor knockout animal model (Non-Patent Documents 3&4). More specifically, the efficacy of Fingolimod based on its immunosuppressive acting is mainly exerted by sequestering lymphocytic cells, which play a pivotal role in immune response, to secondary lymphoid tissues by controlling an S1P1 receptor. Meanwhile, adverse effects such as bradycardia and cardiac arrhythmia are more likely attributed to the agonist activity of Fingolimod at an S1P3 receptor, an S1P4 receptor, an S1P5 receptor, and the like other than an S1P1 receptor. Therefore, the development of S1P1 receptor-selective compounds has been desired.
It is known that there are oxadiazole derivatives (Patent Document 1, Patent Document 2, Non-Patent Document 5), thiadiazole derivatives, thiazole derivatives (Patent Document 3) and the like having an agonist activity at a S1P1 (EDG-1) receptor. Although the selectivities of all of them to a S1P1 receptor and a S1P3 receptor have been described, there is no report on their selectivities for a S1P4 receptor or a S1P5 receptor except disclosing only their measurement procedures. Moreover, there is no report disclosing a compound having two phenyl groups at the position 2 and 5 of a thiazole ring respectively wherein the phenyl group at the 2-position is coupled with a cyclic amino group via an alkyl group.